Citi’s 16th Annual BioPharma Virtual Conference

Sep 9, 2021

Okay, great. Welcome, everyone. I'm Yigal Nakhimovitz. I'm 1 of the biotech analysts here at Citi. Welcome to the panel on autologous, allogeneic, CAR T, CAR NK and more exploring the state of play in cell therapy. And it's my great pleasure to have with me today from Atara Bio, Pascal Tushon, who is the President and CEO from Cariboo Biosciences that recently went public, Rachel Horwitz, President and CEO from Selectus, Andrey Chulika, the CEO and from Grace HelBio, William Kao, the Chairman and CEO. So welcome all of you today. Thank you very much for taking the time. I think as a starting point for those less familiar with each of your companies, maybe we could just go through and do a brief introduction to the company and the pipeline and maybe comment as well on what you see as the strengths and differentiating qualities of your cell therapy platform. So maybe Andre, you want to kick it off? Sure. Well, hello. Thank you very much for the nice introduction, Miguel. I appreciate it. Slightest is a gene editing company at the basis. We've been founded on the concept of gene editing at start. We had the 1st wave of the gene editing product that we started developing back like in the few years ago, I would say like almost 8 years ago on the concept of using gene editing to make allogeneic CAR Ts. And since then, like this has been developing series of product as allogeneic CAR T, We started with the first product that was a CD19 that licensed out Sergei that is currently shared between Sergei and actually when we started with Sergey, it was with Pascal at Serbia at this time, it's a super exciting time and I really like their U. S. Rights to Allogene, so it's the blood currency under the name of ALLO-five 0 1 or ALLO-five 0 1. And then we have the blood series of other CAR T in the space. Recently, we've announced also the launch of a new platform that is a gene editing platform for hematopoietic stem cells and we're tackling the first type of diseases, disease that will be sickle cell disease, but there are a series of other type of diseases we have since the summer of full manufacturing ranging from buffers, DNA, RNA vectors and cell therapies that are manufactured internally. And that's quite a quick overview of select this. Thank you very much, Andre. Rachel, tell us about Caribou in 1 minute. Sure. Thank you, Yigal, for the invitation. Caribou is a CRISPR genome editing company. We were spun out of Jennifer Doudna's lab at UC Berkeley about 9 years ago. And during this time, we've actually invented our own proprietary next generation CRISPR technology. We call it the Chardinnae platform and it has far more specific genome editing than 1st generation CRISPR Cas9. We use this technology today with a focus on oncology. And we're advancing 2 kinds of therapies in parallel. We're developing allogeneic CAR Ts for hematologic malignancies and allogeneic CAR NKs for solid tumors. The key theme that runs across all the work that we do is persistence. We believe that enhancing persistence is key to unlocking the broader opportunities for allogeneic cell therapies. And I'd be happy to dive into more of those details as the conversation progresses today. Perfect. William? Hi. Greycell is founded in China, and we have been developing 2 platforms technology trying to resolve the industrial sort of bottlenecks. 1 is for autologous car, it takes weeks and that's sort of industrial norm. And obviously, that creates not just cost high cost, but also the time to deliver is an issue. And if some of the patients could not wait or some of the patients that disease progress the next stage. So we developed this fast car, which is next day manufactured that are going to resolve some of these issues. And the Tri YUKA, it's a standalone YUKA T, it's gene edited, but we don't use anything else to suppress the allo reactions. Instead, we apply the dual cost, 1 goes to kill the target cell and the other 1 to prevent rejection, sort of dual cost approach. We have multiple pipelines in clinical trial, IIT trial, IND trials and so late stage of early developments. And we also have enhanced CAR for solid tumor and that is based on gene editing. We have published the first IIT studies that is a PD-one knockout, whether it's TCR plus PD-one knockout, it's autologous CAR or mesothelin positive CAR T. And the result is encouraging in the sense of potential autoimmune disease and that's the most worrisome potential side effects. And it turned out, we didn't see any severe side effects. So it gave us sort of baseline of safety tolerability. So now we have a 2nd generation sort of enhanced car and flipped negative signal around and targeting certain solid tumors and also adapting the Claudine 18.2 as a new target. So yes, we now most of people are in China, but we are spreading to South California. Thank you. And Pascal? So Atara Bio is located in California. Atara Bio is a leading allogeneic T cell immunotherapy company with a fully differentiated allogeneic cell therapy platform relying on EBV for eptranbar virus T cells from healthy donors. And we have now 3 programs in the clinic, including what is arguably the most advanced allogeneic cell therapy in Phase III, tab cel, the first in client BTD in oncology soon to be submitted for regulatory approval in the EU and the U. S. We have also in Phase II a potentially transformative therapy for multiple sclerosis, which is now in a randomized controlled trial and has the potential to be the 1st ever therapy in progressive MS to reverse disability. And then we have a pipeline of allogeneic CAR T liquid and solid tumors, the 2 most advanced in terms of allogeneic CAR T going to the clinic next year, 1 targeting CD19 as a potential best in class for B cell malignancies, the other 1 targeting mesotidine for a number of select tumors. Perfect. Thank you. So let's get into a little bit more of a specific discussion about cellular therapy. I'd like to get an understanding from the panel as to what you see as the key hurdles and challenges associated with allogeneic therapies allogeneic cell therapies that is, And how are you thinking about edits to your cell therapies to overcome these challenges? So curious, Andrea, you want to start? Well, there is always pros and cons in any type of approach. And of course, 1 of the strengths of polyglucos therapies is that the cells are not rejected unless like the protein gives really new responses that were rejected. But the fact is that there is longer persistence due to the fact that it's tolerance. But this is a double edged sword. It's a double edged sword. It's good if you're working, for example, in B cell malignancies because you can't live without B cells, it's fine. But finally, it reduces the space of the use of these type of technologies essentially for like NHL or ELL etcetera, which remains something that is of a high value, but very limited. A lot of different targets, you cannot live with the car remaining in the body for years years and the car targeting target and this it has to be something that persists enough to cure all the tumor and have to go afterwards. For example, if you're targeting targets such as methylam that would be familiar to Pascal or if you're targeting a target such as CD123, which is expressed on milli progenitors, you cannot survive without milli progenitors. So you have to hit the target and go. So it makes more sense if you want to extend this type of technology to series of different type of tumor associated antigens and applications to something that would be turned off at a time. And that's why I strongly believe that there is a space for autologous therapies in general, But the more it will go, the more I think autologous therapy are going to be very powerful in hospitals. But a real industrial product that will be commercialized, renovated, etcetera, makes it difficult to spread this through series of different type of indications and then industrial process at the end. It makes more sense to try to edit the cells, try to work on their fitness state, try to have them extended over a period of time and potentially develop an application of redosing person the patients such as a consolidation therapy instead of thinking of what has happened in the beginning of like let's say, TTL-nineteen, which is today Cambria, a single shot, people get out from like the disease and walks away and everything is fine. This is not the way these type of therapies are going to evolve in the future. It's going to be more sophisticated than this. And I believe also it's going to be probably also potential of combo therapies at the end. Okay. Thanks. Rachel, do you want to give us your perspectives on what attributes are important to consider in designing a allogeneic cell therapy? Yes, absolutely. And I'll hit on a similar theme as Andre did. Of course, 1 of the key differences for allogeneic CAR Ts relative to autologous CAR Ts is that they are foreign and they will be subject to this fairly rapid immune mediated rejection. And so we are really focused at Caribou on enhancing the persistence of these cells. To Andre's point, it's not about keeping them forever, but it's about keeping them long enough to have sufficient and appropriate antitumor activity. At Kervo, we think about persistence in multiple orthogonal ways. Our lead program CB10 is in a Phase 1 study now and it's an allogeneic anti CD19 CAR T. To the best of our knowledge, it's the first allo CAR T into the clinic with a PD-one knockout. And our reason for removing PD-one using our genome editing technology is to prevent premature T cell exhaustion to maintain these AlloCAR Ts in a high antitumor activity state for a longer period of time. Of course, this is 1 approach for persistence. An orthogonal approach is to actually prevent that rapid rejection by the patient's immune system. And that's the strategy we take with our second program, CB11. It's an allogeneic anti BCMA CAR T on track for an IND filing next year. For this program, we manipulate HLA Class 1 presentation through multiple genome edits. We actually remove all of the in this Class 1 presentation by knocking out a gene called beta-two microglobulin or beta-two ms. And then additionally, we site specifically insert a transgene that encodes a fusion of beta-two ms with HLA E. And this ensures that our product candidate is decorated only with HLA E with an eye to preventing both the patient's T cells and importantly their natural killer cells from rapidly clearing these therapies. These 2 strategies are of course distinct and orthogonal and could potentially be additive depending on the tumor target. And we're today exploring the opportunity to actually combine both of these in a single product candidate in the future. And William? So we are developing both autologous and allogeneic. And to be very frank, at this moment, we do see and enjoy both advantage of both platforms. And it's not conclusive based on our clinical experience. We have 15 products going through clinical IT trial to derisk the innovative designs. But what we see with each platform, there are clear need for each platform, autologous, for obvious reasons, right? And also for very clear reasons, and I agree with both of you. The convenience and redosing as allogeneic and especially for some patients, you just can't have enough white cell from these patients for autologous CAR T, but also the cost and the waiting period and everything that goes to support allogeneic. But again, as Audrey pointed out, the persistence, that is the whole industry. This is the challenge. And whether you want to be loan persistence or you want to deal with potential issues, so you're putting switch in and then deal with potential CMCs. There's a lot of issues, but I think the future definitely is allogeneic, but the question is still there. How long you want to keep these as a persistence and especially moving to solid tumor side? And I don't believe that with a few shots of allogeneic CAR T, you can clear up the tumor mass or in my phasing, tumor lysis syndrome at that kind of fast speed. But we're testing like everybody else. We are moving UCART T for multiple myeloma in addition to autologous. So we are testing both, see find their fit indications and situations, And that's where we are. Thank you. I don't know, Pascal, did you want to add anything to that? Maybe 2 things to add. 1 is, I certainly agree with William that Allogeneic, the future, as well as with Andre and Rachel that persistence and the adaptive persistence of what you want to have in terms of durability of response is a key aspect there. Now we're looking at that with very different technology based on clinical experience, because we've already treated more than 300 patients with our platform, and we've been proving that it is safe to use our platform in these patients, but there is no safety issue with these EBDT cells coming from healthy donors. And we also proven that the cells are persistent enough for durable response. Now what we're doing in terms of additional gene editing is really to further stimulate what I call the functional persistence, which is the ability of these sales not only to persist, but to persist in a state of activation and memory that allows them to be functionally persistent for us. And we do that not only leveraging EBT cells from healthy donors, but also in adding a new costimulatory domain called 1XX that has been invented by Michel Sadler and Memorial, as well as a PD-one dominant negative receptor for solitumens on these cells. And we have data there at the preclinical level on this PD-one DNR and soon we will present that in a few months at a clinical stage that shows that this is helping the cell not only to persist functionally, but also to resist the immunosuppressive environment in solid tumors. And the final point I'd like to make is the importance of robust scale up and manufacturing. And we've proven that already. We are making now with a new technology some of our product in steel ton bioreactor, where depending on the dose we can make like with 8, 188 or MS product, we know we can make up to 20, 000 doses from 1 Nucor pack. So we are so advanced being in Phase 3 and Phase 2 and close to submission from 1 of our product that we've been able to develop a very robust manufacturing process that is scaled up at a sufficient size to be able to treat patients in a very simple way. And again, we have a very large clinical experience with more than 300 patients treated already. Thank you. And you all sort of touched on this theme already in terms of the interplay between autologous and allogeneic. As you mentioned, William, allogeneic is the future. But that being said, I'm just curious more specifically if any of you wanted to comment on whether autologous whether there still be a role for autologous in certain scenarios clinically? Maybe I can start there and saying because I work on both as you know, you got there. I think certainly the autologous are today approved product, non allogeneic product is approved. So certainly they have a place today and they are saving lives today in the CD19 and DCMS space there. Now what's happening is that we see academic teams exploring new target with Autologous, and I think that's great that academic teams can do that. It's very easy for them to do so, and that's going to derisk a number of targets for many aspects there. But I don't see a future for Autologuards moving forward for CAR T. There might be a future when you need a kind of oligoclonal TCRT response there, where it might be today with our current technology, still a bit challenging to make a product made of very different type of TCRTs there. But we will find a way to get to that point. But that's certainly where the other space today is if you don't have a CAR T or 1 TCR only, but you want to have multiple TCR to address a particular tumor there. I cannot agree more with Pascal actually on what she just said. Autologous CAR T today saves lives every day with fantastic products such as Hemria, yet Carta's great product. There is like also 2 other products that came out from like 1 from DMS, 1 from Mike Johnson and Johnson Legend, like the TCMA CAR T. It is saving lives. But it is sustainable over time to do it in a way it's done industrially is a complication. And I also agree very much with Pascal on 1 point, it will remain the therapy. But I think at a time it will loop up and go back to hospitals and academic centers where it was born actually allogeneic tolerance CAR T were essentially developed by like Urisio, Pennsylvania, the NCI, MSK, like strong Kettering, etcetera. And it will probably go back again in hospitals when you have a single very specific type of treatment and will be slowly replaced completely by allogeneic. So it's kind of a wave, but this wave will disappear. And it will remain, but it will remain as bone marrow transplant as a business for hospitals such as MD Anderson, it's a huge business for them. But it's not a business for pharma companies or biotech company under the long run. It could be on the short run. Now when you discuss with most of the physicians that do sell therapies, 1 of the things they will tell you on a regular basis, it's becoming a total nightmare for most of them to treat patient a positive therapy. Aperasis center are totally saturated. The number of clinical trials ongoing are huge all over United States, all over the rest of the world is becoming a complexity in logistics and market access for these things is impossible. So it's not sustainable if you want to expand this to more than what it is today and you will have to find a replacement to try effectively to tackle cancer. This is not the way to go. Very interesting. Rachel, did you want to add anything? I think my co panelists have hit the highlights. Okay, very good. All right. Well, moving on then, I'm curious how each of you are thinking about the relative interplay between CAR NK versus the CAR T cell therapies. Where does CAR NK have an advantage over CAR T and vice versa? Are there settings where potentially you could use both in a combo strategy? Curious anyone's thoughts on that? Yes. I will be happy to dive into that 1, Yigal. Okay. So at Caribou, our mindset is twofold as we think about these 2 different kinds of therapies. We focus on hematologic malignancies using allogeneic CAR Ts and we focus on solid tumors using allogeneic CAR NKs. So why? As we look at the CAR T field and especially the autologous Ts that we've just been discussing, they're obviously tremendous proof of concept in terms of the power of the immune system to have anticancer activity. I think that emerging field has also demonstrated how challenging it is to harness T cells in particular to have sufficient and appropriate antitumor activity in the solid tumor setting, where hematologic malignancies are challenging, solid tumors are even more challenging As we think about the need for trafficking and targeting penetrating the tumor overcoming the immunosuppressive tumor microenvironment and dealing with the underlying heterogeneity of solid tumors. So at Cariboo, our perspective is that natural killer cells are a better start point than T cells to try to tackle that litany of challenges. And we see the natural killer cell as the start point and not the endpoint. We're actually able to use our genome editing to make a variety of different edits to try to tackle a number of these different issues, including introduction of a CAR for antigen specific targeting. In order to do all of this, we actually start with iPSCs. So at Caribou, we take iPSCs, edit them in a variety of ways to tackle these challenges and then differentiate them using proprietary protocols that we've developed into natural killer cells with anti tumor activity. So we believe that this will be a really exciting and compelling approach to address the solid tumor compartment, which is obviously a huge unmet need as we think about the role of cell therapies in cancer care today. Thanks. Maybe I can bring a different view and I think that's what the panel is for probably is to have divergent views as well as some time aligning. I mean, what we believe at ATRI is the T cell or key cells, even in solid tumors. I mean, the reason why on TPD-one and on TPD-one are working is because they allow T cell to do their work. And I think there have been so much experience now with all these checkpoint inhibitors about allowing the T cells to really do their work and combat the cancer cells that we still believe that T cells are the key for both solid and liquid tumors. The challenge we see with NK Cells is that they are fully differentiated sales that are short lived in vivo, they're not supposed to persist. T cells are there are the memory cells, they are the 1 having, especially when you have a phenotype in your product that is more into the central memory cells, you have cells that are supposed to persist long to be able to fight infection and you use that to make sure that they can persist long enough for addressing the tumor there. NK cells are not supposed to stay and they are not supposed to persist there. And that's why there is a lot of engineering techniques there. But if you look at what has been 1 of the key study to support was the great study by Kathy Resvani at MD Anderson, what people tend to forget is that in that paper, if you read the paper carefully, you understand that these cells that were used in patients and were targeting CD19 CAR were in fact HLA matched, partially much for most of the patient, 9 out of 11. Anyway, key mismatch and key mismatch is important for an NK cells to be fully put on there. So they were not fully allogeneic from that point of view. And even though they were not having that durable response that is being seen with CAR TBE. So we strongly believe that NK sales are possibly interesting and might give some short term impact, but not to address the importance of durable remission in solid and liquid units. Sorry, back to the question. Yes. Let me kind of switch back a little bit to defend the autologous car a bit since we're doing both. There's reasons. We do have strong conviction with the autologous car. You got to give any technology product lifecycle sufficient time. If you look at any new technologies come and go, and what you get from clinical, it's real. It's solid. So what we've seen, autologous car, especially I'm not promoting fast car, but autologous car does give you long persistence without concern of safety issue. And some of what we see from our patients, the CAR T can persist a year and year and a half. And sometime, they can pop up again, maybe responding to antigens, maybe not. But there is no off target, there is no other concerns, and this is the beauty. Now the CRS neurotoxicity can be resolved and our this dual CAR for multiple myeloma, no neurotoxicity. And 1 injection, you think about it, 1 injection in 5 days, the issue is gone. All standard of care for CIS 1 to 2 grade, it's gone and patients are recovered. 95% of patients achieved CR and for a long time. That's a miracle. Now we cannot cover it up with issues. Autologous does have issues, but right now, this is a proven platform. Now again, like everybody else here, we embrace the allogeneic. What we see from the program of TLL targeting T cell leukemia cells. And our goal was trying to 1 shot and hopefully last long without stem cell transplantation. So that was the design for that study. But it turned out only 1 patient last mean, CR without any events more than 18 months, but only 1 and the rest of patients, 6 months, 8 months or 3 months, and they relapsed. Now for TLL, such aggressive disease, this is remarkable because there is no other standard of care, effective care. But this let us think that, well, the design may be the persistence. Maybe we need to put certain signal transactions, maybe make it more persistent and so on. There's a lot of work need to do. So our 2nd generation UCAR T for B cell malignancy is hitting clinical trials. And this is the hope, but I will not hope that much that this is going to resolve, will achieve the same persistence as autologous CAR T. We have a few years to go to manipulate the molecules that are important for persistence without increase the side effects. And I believe this is where we are. Now back to the NK, the attractiveness, I think, is really drive by the hope of safety. The NK is really safe. And regardless of core blood with little mismatch or IPS derived. And I'm really excited about the future of IPS because you can manipulate so much at this master bank without affecting the cargo side, without affecting the JING transaction or Kain K or anything that you want to add on at later stage. That's the beauty, 1 batch, much bigger than Yucate. Right now, we can make 300 doses of Yucate, but that's not it's not ideal, right? We should make more to make a more batch less batch, batch variation, but IPS is attractive. But the current data, at least leading programs by other companies that you need actually combination therapy, right, either additional antibody or IL-two and efficacy is kind of at the par at the current autologous CAR T therapies. It is not sexy yet. There is a hope you can redose, but then lymphodepletion is trick. How many times you are doing lymphodepletion? And can we live without antibody assistance? And if this is the hope for solid tumor, what kind of antibody combination with NK would pull the trick? So there are unanswered questions or need to a lot of work need to be done testing clinical. That's our view. Okay. Thank you, William. Just a little word about like the in case, Just to come back to what you just said, Gal, it's combo and like what just William said also combo is definitely the enemy here is definitely cancer. So anything good to try to tackle cancer is great. I agree with Pascal and also Rachel. I agree with everyone because everyone has an angle. But finally, the answer is always about the ability to try to blow out the tumor itself. So for example, if you want to go against a solid tumor, what's interesting in a T cell, they're super expandable. So they can expand very powerfully. And what Pascal said definitely makes sense. And like the PD-one checkpoints inhibitors are very active on T cells, they're not active on NK. On the other side, you see that NK can be very good in cleaning out some part of the solid tumor. So why the concept of trying to exclude 1 over the other, etcetera, and not trying to include everything in a potential therapy? For example, we're developing a CAR that targets fibroblast as a stated proteins and cancer associated fibroblast that makes this protection for the tumor. You blow it out with T cells, you can add checkpoint inhibitors. It depends the way also you design your T cells. It could attract the patient T cells after when the immune system goes back and can turn the hot like culture into hot tumor and potentially have a very strong effect on some most of the solid tumor that are responsible to these type of checkpoint inhibitors. And then finally, you can potentially have an NKCAR injection to clean up the situation afterwards. As we have to keep a focus not on the technology we're using, but really on how to try to eradicate the tumor cell of the patient as cleanly as possible. And I think all these approaches are very comprehensive. Now they have to be doable, but that's the concept that we're developing. And I think that tells me like in care are really interesting. The simple fact that it's more easy to differentiate them from like IPS cells and their access, etcetera. So you can do all the engineering you want to do before you can access this. But definitely T cells are the gate to these cell Thank you. Thank you very much, Andre. And William, you brought up lymphodepletion, which was on my list of questions. I'm curious how each of you are approaching lymphodepletion question, what strategy or strategies you are using to do the lymphodepletion to improve engraftment? Curious if you could comment on that. Thank you. I can get started. So we have done a lot of things in this space. So, laser depletion, of course, we have like the standard, which is CyFlu from all autologous space that have been very extensively developed. It doesn't work without it most of the time, because you have to create space for yourself to expand and even if you have a polyester, if you don't do a fast food for being graphing will not happen so well. So we've done CyFlu, but obviously we have a second protocol. So we made a comparison in the protocol for like UCAR22, end UCAR123 where you do CyFluid and CyFluid and we add alemtuzumab, which is a multiple antibody that would maintain the immune system there for a long period of time to the T cells to expand. And we've seen with the like your CAR T19 or CD19 results, BCMA results that you can have a long persistence using the adenov alantuzumab can see the CAR like even 3 months after injection and pretty long duration over 6 months like to 1 year of complete remission post the use of alemtuzumab. So alemtuzumab brings a lot to the lipid depletion regimen and the way to dose this is translating prepared for the Phase 2 and the expansion pivotal trial with our partners. On the other side level, also a new approach that we've also presented at the last ASGCT, which is cell lymphodepleting CAR. So CS1, the target CS1 is present on all immune cells, NK, T, macrophages, whatever, B cells, etcetera. So we do side flu first, but dialing up or down the side flu to have more cells in order to enhance the cell to start the expansion and the anti tumor side makes it extremely interesting. And you can see over 100, 100 and 4, 105 days after the injection of CureCard CS1, the cells persist for a long period of time. So SaaS wants to be bleeding car even though it's not easy to wield, it's something that is conceptually very, very interesting. And then finally, what would be interesting is like, for example, the approach that has been described by Rachel that would also be developing very extensively, which is the knockout of beta to microglobulin, which could open an NK attack versus beta-two microglobulin replaced by HLAE, which could block also NKs with HLAE. And here it's interesting to see if you would lymphodeplete or not. And that's something that should be done. I guess that you will have to lymphodeplete. But it's a very, very important part of the secret sauce behind the CAR T development in general. We have Yigal a slightly different experience there because we have with TAPCELL in particular and with AT1, 88, but with TAPCELL specifically on hundreds of patients, an experience of expansion and persistence without the for the patient, because the patient are being treated with no pretreatment, 5 to 10 minute infusion and that's it, only a 2 hours monitoring. And that explains shows that the product is still able to expand and persist despite the fact there is no need for depression. Of course, these patients that we are treating, most of them are immunocompromised, but it might explain what's happening in this patient there. But it's also linked to the fact that we have this partial HLA matching for the product there and to the patients that might also allow more persistence. Now the other experience we had is coming from Memorial, we did this clinical proof of principle that using an allogeneic CD19 EBV GALTI, you then have sufficient persistence to have very long durability of remission. In the patient they treated, they had an 83% complete remission, that was maintained for more than 2 years. And there'd be no loss of response over 26.9 months median follow-up there. So that's really the 2x plan, but in that case, they had so many for the patient with CyFlu, a typical 1. So what we think is that it depends very much on the status of the patient and how long you want them to persist. There are some of our product allogeneic T cells where we don't need it for the patient and some others where we need some level of it for the patient, certainly not too long and not too heavy. And maybe I'll dive in here as well, maybe a viewpoint in between these 2. So for our product candidates, we believe lymphodepletion is critical. It's a message we've heard from our SAB, from KOLs time and time again. And the perspective we hear from them is that if you don't sufficiently lymphodeplete for these kinds of allogeneic CAR Ts, it really doesn't matter what bells and whistles you put on the product candidate using your genome editing if you don't create that window of opportunity for sufficient engraftment. So our strategy is to use a CyFlu combo. However, it is a more significant, more stringent approach than others have used in the allogeneic setting. So it leads to a deeper lymphodepletion. It's a protocol that was developed about a decade ago at the NIH. It's been used for autologous CAR Ts and for TILs. So there's quite a lot of safety data collected on it. And we believe it will be important and impactful in the antitumor activity. Our experience echoes the importance of lymphodepletion. But also, we clearly see the correlation, the level of lymphodepletion versus expansion of UCART Ts. It's clear. More you do and then it's definitely creating environment to favor expansion of UCART Ts. But then the cost may be potential infection, and that it's a very clear clinical science there. The key questions, I think, whatever we do, I think the goal is we want to win over autologous CAR Ts with persistent durations and the CIS side effects. And I think that's the key and we are working on it. And I think what we're trying to do is how long we need, what is the potential downside for that persistence we may face, we may need to explain to regulatory bodies. And I think the team, I think in a few years, we'll have a more perfect solution for heme. For solid tumor, I think even for autologous, we need to break through these barriers that Rachel mentioned, infiltration, particularly in tumor market environment. How do we let the UCART T to in harmony with the tumor market environment? I think that's something we need to work on. And we are working on that and hopefully, we have data in the 12 months. Okay. Thank you very much. Now all of you have run or are running Phase I studies in with cell therapies. So I'm curious if you could talk about some of the pitfalls for running early stage Phase 1 trials with cell therapies. What are some of the pitfalls that you would advise someone entering into the same development strategy? Any thoughts there in terms of what to avoid with the early stage clinical trial with the cell therapy? Maybe 1 thing to highlight is, I think, site selection is key, right? As we think about actually deploying these kinds of therapies and as you and others have highlighted in the discussion today, the potential risk for CRS and other side effects, there are locations across the United States and now across the world who have deep expertise in using these kinds of cellular therapies and being able to quickly detect the kinds of side effects that can be well managed and well treated. So certainly, our experience has been that it's very beneficial and helpful to work with sites who are deeply expert in these arenas. I couldn't agree with Rachel anymore. When we had doing this clinical IIT in China, the variation among hospitals is significant, especially the experience dealing with CIS. And with same degree of CIS, hospital A could who have more experience, who can deal with the CIS in a standard way. And then hospital with less experience may escalate the therapy easily so that you easily rate Grade 3 because if you use vasoprexone. So that need to be, I think, experience of the doctors and hospitals is the key to give you quality data Phase 1. But I think more challenging to us, it is our experience is when you have a normal design, for example, a fast car, the dose that require for to achieve similar efficacy is about 50x lower or at least 10x lower. And what we do in the beginning, trying to submit the application through asset committees, and they are strongly against from we start from low dose, typical dose escalation. That is the challenge, and they do not want to let patients miss the opportunity of the benefit of potential therapy, and they want we start a middle dose. They don't want to start low dose. They think it's not beneficial to patients. That is our challenge. So and after first 1 patient, if they are convinced to see a decent proliferation, and they would agree to escalate higher dose or vice versa. And those are our challenges. I think I fully agree with Rachel and William there. We have a different set of challenge because we are running a Phase III study with allogeneic cell therapy. We're also running a placebo controlled Phase 2 outside of oncology and neurology. So that's also leading to very specific challenge and what you need is of course safety, but you need also to be able to treat patient in outpatient clinic, like in our multiple sclerosis trial, we're not treating patients only that are hospitalized, they're all in outpatient clinic, they come and go for their treatment, like for monoclonal antibody. And this is a new experience for many of these doctors, so we have to train them, but that's very important because we believe it is the future of allogeneic cell therapy that this therapy will be used like monoclonal antibodies in the future, depending of course on the type of patients, but in some patients could be used in outpatient clinic with just a 2 hours monitoring due to the safety profile that we can achieve there. So moving to Phase 2 and Phase 3 is leading to the need to go beyond expert centers and to be able to have a safety profile that is remarkable enough to be able to be used in many, many sites across the world. And we're running these studies across 3 continents in the U. S, in Europe and in Australia. And we've seen that with good training of these investigators, they are able to use cell therapy, even neurologists are able to use cell therapy in a very safe and efficient way. And of course, oncologists and hematologists are more used to that, but they really can treat patient in outpatient setting with allogeneic cell therapy. Okay, great. We're running out of time, but I'll do a quick lightning round, if you'll allow me. Just go around the horn here and ask some company specific questions, maybe starting with you, Pascal. Could you just help set expectations for the data for the allogeneic mesothelin CAR T, the ATA-two thousand 271? I believe you're going to have data in the Q4 of this year. Can you just give a quick overview of what we should expect? Yes. So this product ATA-two thousand 271 is targeting mesothelin, still the autologous version. The allogeneic goes to the clinic next year. But it's going to be the first time ever in patients that somebody has used a PD-one dominant negative receptor CAR T as well as 1XX as a co stimulatory domain. So that will be about safety, some data efficacy, but that will be just the first 2 cohorts, so that's rather limited. But very importantly, we'll have data on expansion and persistence of the sales. So that will be important because of the PD-one dominant negative receptor and the OneXX as a cost in domain. Thanks. And Rachel, you've just started recently the Phase 1 ANSLLAR study in BNHL for your lead product CB010. Curious what you would see as the criteria that you need to see to achieve proof of concept in that Phase 1 trial? Yes, great question. So much like PASCAL, this is a first example of a program with a particular kind of modification for persistence. In this case, this is the first allogeneic CAR T to the best of our knowledge with a PD-one knockout. And so obviously, we'll be learning not only specifically about the impact of this program in the BNHL setting, but more generally the impact of the PD-one knockout and understanding in what other product candidates it might be important in the future. This is a Phase 1 study. So of course, it's officially about safety and tolerability. But clearly, the benefit of working in the cell therapy space is the opportunity to collect and ultimately disclose emerging efficacy data as well. So certainly excited to share the first cut of data from this ongoing study sometime next year. Thanks. And Andre, for you, obviously your pipeline has been heavily focused on hematologic malignancies, but I know you've said in the past solid tumors are part of your long term plan. So could you talk a bit about transitioning the pipeline for your cell therapy to solid tumors and your strategy there? Thanks. Yes, sure. Actually, we have presented 3 products that are going to go into clinic starting next year, probably going to stage them because it's going to be a lot. Well, we have our first allogeneic mesothelin CAR T that we're pushing into the clinic somewhere like in 2022. It had like a specific interest in there, which is the knockout of TGS beta 2R receptor to try to remove all the negative feedback loop that you can have in the tumor, the solid tumor microenvironment. So the knockout of TGF beta 2R can provide some insights on the way the cells to behave for these type of solid tumors. It's a very exciting CAR. We have excellent results so far in pre clinic and it will be pushed forward. The next CAR TU for solid tumor that we're pushing forward is this thyroid assocetor protein to try to turn cold tumor into hot tumor that could be done potentially like in clinical trial in combo that could unleash a lot of different targets of tumors that do not respond to checkpoint inhibitors and in this case could potentially become checkpoint inhibitor potent and that could open the gate for a lot of different type of application in this array of different type of solid tumor where fats are really playing some key role. And finally, the last but not least, which is a super interesting car, very sophisticated that can that we're going to push in triple negative cancer, which is MOCK1 that have 3 knockouts, 2 knock ins and the TGA EBITDA 2 are down in the negative that will be expressed there. And that's probably for later. It's still early stage, but at least these 3 cards are in the pipeline in terms of where we push into clinic starting next year. Okay, great. And finally, quickly for William, just talk about the next day manufacturing and does next day manufacturing in your view render the off the shelf therapies as potentially unnecessary or will there still be a role for off the shelf therapies in a world where we have next day manufacturing? First of all, the fast car or the next day manufacturer still require it is a person to person. So the QC is each person. It is unlike the UCART T, 1 batch QC, that's it, right? So there is a clear difference here. And of course, the fast car is still autologous and it really carries the advantage of the autologous CAR Ts. And but we are very excited to see the safety profile of a dual car, and it gets so much to manipulate to make a safer but highly efficacious dual cars. And as our data clinical data shows, our high dose now so far has been 11 patients, 100% SCR and with a sound safety profile without any neurotoxicity. And we decided to move into frontline therapy for high risk population. And that's a sort of game changer. If that happens, so we got a license to move on frontline, and we're very excited and hope we can present the data very soon because this is the representation of CAR T therapy in frontline and that's exciting. Well, thank you all, Pascal, Andre, Rachel and William. Thank you all so much for a very lively discussion. We appreciate it very much. Good luck with the rest of the conference and we'll be in touch. Thank you,